Leukapheresis day 11 to 13: the target cell number for each reinfusion was 2 x 106 CD34+ cells/kg body weight. Leukapheresis may not be required in cycle 2.

* Mesna dosing: daily dose of mesna to be calculated to equal 60% of the total daily dose of ifosfamide, administered as three bolus doses given 15 minutes before and 4 and 8 hours after administration of each dose of ifosfamide.

Frequency:

14 days

Cycles:

2. This treatment regimen consists of two parts: 2 cycles of TI (Paclitaxel and Ifosfamide) followed by 3 cycles of CE (Carboplatin and Etoposide) with PBSC autologous transplant.

The supportive therapies (e.g. antiemetics, premedications, etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Cycle 1 and 2

Day 1

Dexamethasone

20 mg (PO)

the night before and the morning of chemotherapy

Loratadine

10 mg (PO)

60 minutes before chemotherapy

Ranitidine

150 mg (PO)

60 minutes before chemotherapy

PACLitaxel

200 mg/m2 (IV infusion)

in 500 mL sodium chloride 0.9% over 3 hours

(in non-PVC containers only)

Day 2 to 4

Mesna

400 mg/m2 (IV infusion)

THREE times a day in 100 mL sodium chloride 0.9% over 15 minutes, starting 15 minutes before ifosfamide infusion and then at hour 4 and 8 post ifosfamide infusion

Leukapheresis day 11 to 13: the target cell number for each reinfusion was 2 x 106 CD34+ cells/kg body weight. Leukapheresis may not be required in cycle 2.

* Mesna dosing: daily dose of mesna to be calculated to equal 60% of the total daily dose of ifosfamide, administered as three bolus doses given 15 minutes before and 4 and 8 hours after administration of each dose of ifosfamide.

Frequency:

14 days

Cycles:

2. This treatment regimen consists of two parts: 2 cycles of TI (Paclitaxel and Ifosfamide) followed by 3 cycles of CE (Carboplatin and Etoposide) with PBSC autologous transplant.

The supportive therapies (e.g. antiemetics, premedications, etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Cycle 1 and 2

Day 1

Dexamethasone

20 mg (PO)

the night before and the morning of chemotherapy

Loratadine

10 mg (PO)

60 minutes before chemotherapy

Ranitidine

150 mg (PO)

60 minutes before chemotherapy

PACLitaxel

200 mg/m2 (IV infusion)

in 500 mL sodium chloride 0.9% over 3 hours

(in non-PVC containers only)

Day 2 to 4

Mesna

400 mg/m2 (IV infusion)

THREE times a day in 100 mL sodium chloride 0.9% over 15 minutes, starting 15 minutes before ifosfamide infusion and then at hour 4 and 8 post ifosfamide infusion

The product information states that premedication is required for this treatment.
Please refer to the treatment schedule for the suggested premedication regimen.
This may be substituted to reflect institutional policy.

Antiemetic therapy should be administered throughout the duration of the chemotherapy protocol and to cover delayed nausea. The acute and delayed emetic risk of multi-day chemotherapy protocols will overlap depending on the individual drugs and their sequence of administration. More or less antiemetic cover may be required.

Ensure that patients also have sufficient antiemetics for breakthrough emesis:

Metoclopramide 10 mg three times a day when necessary (maximum of 30 mg/24 hours, up to 5 days) OR

Commence on admission or at start of conditioning regimen and continue throughout transplant. Due to profound and long lasting inhibition of gastric acid do not administer concurrently with posaconazole syrup or itraconazole capsules.

Hydration regimen pre high dose cyclophosphamide or ifosfamide (as per local guidelines).
There is limited evidence and no consensus regarding hydration regimens and mesna dose, route or timing of administration.

Assess prior to each treatment. If a patient experiences grade 2 or greater peripheral neuropathy, a dose reduction, delay, or omission of treatment may be required; review by medical officer before commencing treatment.

All transplant recipients are to receive irradiated blood products. Additionally, those patients who are CMV serologically negative are to receive CMV negative or leucodepleted blood products (i.e. CMV safe), as dictated by local clinical policies.

Evidence for dose modifications is limited, and the recommendations made on eviQ are intended as a guide only. They are generally conservative with an emphasis on safety. Any dose modification should be based on clinical judgement, and the individual patient’s situation including but not limited to treatment intent (curative vs palliative), the antineoplastic regimen (single versus combination therapy versus chemotherapy versus immunotherapy), biology of the cancer (site, size, mutations, metastases), other treatment related side effects, additional co-morbidities, performance status and patient preferences.Suggested dose modifications are based on clinical trial findings, product information and reference committee consensus. Non-haematological gradings are based on Common Terminology Criteria for Adverse Events (CTCAE) unless otherwise specified. Renal and hepatic dose modifications have been standardised where possible. For more information see dosing considerations & disclaimer.

Note: All dose reductions are calculated as a percentage of the starting dose.

If concurrent use is unavoidable, monitor closely for efficacy/toxicity of both drugs.

Digoxin

Antineoplastic agents can damage the lining of the intestine; affecting the absorption of digoxin

Monitor digoxin serum levels; adjust digoxin dosage as appropriate

Antiepileptics

Both altered antiepileptic and antineoplastic levels may occur, possibly leading to loss of efficacy or toxicity

Where concurrent use of an enzyme-inducing antiepileptic cannot be avoided, monitor antiepileptic serum levels for toxicity, as well as seizure frequency for efficacy; adjust dosage as appropriate.
Also monitor closely for efficacy of the antineoplastic therapy

Diminished response to vaccines and increased risk of infection with live vaccines

Live vaccines (e.g. BCG, MMR, zoster and varicella) are contraindicated in patients on immunosuppressive therapy. Use with caution in patients on non-immunosuppressive therapy.
For more information; refer to the recommended schedule of vaccination for cancer patients, as outlined in the Australian Immunisation Handbook

Day 1

Prior to the conditioning chemotherapy being administered, a check must be made with the stem cell lab to verify that there are stem cells available for the patient, and a confirmation of date and time for the infusion of the stem cells.

Day 2, 3 and 4

Note: A large volume of intravenous fluid may be given with this protocol. If weight increases by more than 1 kg from baseline or fluid balance becomes positive by one litre or any other signs of fluid overload are present, review by medical officer (diuretics may be required).

Day 5

Note: Filgrastim may not be required following cycle 2 if enough stem cells were harvested in cycle 1.

Filgrastim

filgrastim is to be administered commencing on day 5 via subcutaneous injection in divided doses (morning and evening) until stem cells have been harvested.

it should be clearly documented and communicated to the persons responsible for monitoring the CD34+counts and notifying the patient and all other appropriate healthcare professionals when collection is anticipated.

arrangements regarding leukapheresis are usually made by the BMT Coordinator or designated nurse.

Prophylaxis medications

Patient information

The side effects listed below are not a complete list of all possible side effects for this treatment. Side effects are categorised into the approximate onset of presentation and should only be used as a guide.

Immediate (onset hours to days)

Hypersensitivity reaction

Anaphylaxis and infusion related reactions can occur with this treatment.

Ifosfamide induced encephalopathy has been reported in 10 to 30% of patients receiving high dose ifosfamide. Common symptoms include confusion, ataxia, weakness, seizures, somnolence and hallucinations. Onset may be 2 to 48 hours after commencing treatment. When reversible, symptoms usually resolve within 1 to 3 days.

Bone pain, usually in the lower back or pelvis, associated with colony stimulating factors (filgrastim, lenograstim, lipegfilgrastim and pegfilgrastim).

Haemorrhagic cystitis

An inflammatory process, characterised by diffuse mucosal inflammation with haemorrhage involving the entire bladder. Patients are at risk following treatment with cyclophosphamide, ifosfamide and radiotherapy.

Erythematous and ulcerative lesions of the gastrointestinal tract (GIT). It commonly develops following chemotherapy, radiotherapy to the head, neck or oesophagus, and high dose chemotherapy followed by a blood and marrow transplant (BMT).

Typically symmetrical sensory neuropathy, affecting the fingers and toes, sometimes progressing to the hands and feet. It is associated with several classes of antineoplastic agents. These include taxanes, platinum-based compounds, vinca alkaloids and some drugs used to treat multiple myeloma.

The majority of men with germ cell tumours (GCTs) are cured with surgery, radiotherapy and conventional dose chemotherapy appropriate to the location, histology, stage and biochemical markers of their tumour. For those patients who relapse or are refractory after optimal conventional chemotherapy the two major salvage approaches are high-dose chemotherapy (HDCT) with autologous stem cell transplant (ASCT) or conventional-dose chemotherapy. There are no randomised controlled trials (RCTs) to establish efficacy in this setting although considerable level III evidence supports the use of HDCTrrr. Patients with relapse of primary mediastinal non-seminomatous GCTs represent a poorer prognosis subgroup in which there is limited evidence for the efficacy of HDCT r.

A large retrospective analysis of 1435 evaluable patients compared the role of HDCT versus conventional dose chemotherapy (CDCT)r. Overall, 773 patients received CDCT and 821 patients received HDCT. HDCT was associated with improved 2-year PFS (50% vs. 28%, p<0.001) and 5-year OS (53% vs. 41%, p<0.001). The authors conclude that the results suggest a benefit from HDCT but highlight the need for a large prospective randomised trial.

Current salvage HDCT regimens can achieve durable remissions in 30-60% of patients, depending on patient selection and the timing of treatment (initial salvage vs. later in the disease course). Studies have demonstrated that sequential cycles with less intensive HDCT regimens are less toxic and possibly more effective than single cycle more intensive regimens. A randomised trial conducted by the German Testicular Cancer Study Group compared the efficacy of sequential vs. single cycle HDCT in the salvage setting by randomising patients to either VIP x 3 followed by 1 cycle of HDCT consisting of carboplatin plus etoposide plus cyclophosphamide or VIP x1 followed by 3 cycles of HDCT, consisting of carboplatin plus etoposider. Unfortunately, there was unacceptable toxicity in the single HDCT arm such that the trial closed prematurely and differences in efficacy could not be assessed. This and other recent studies have established the standard-of-care for salvage HDCT to consist of two to three sequential cycles of carboplatin plus etoposide, administered 3-4 weeks apart.

The choice of conditioning agents for high dose chemotherapy varies among institutions. While there have been no randomised studies addressing the optimal conditioning regimen for GCT patients undergoing HDCT, high dose carboplatin and etoposide regimen is the conditioning regimen best supported by the available evidencerr. Limiting the regimen to two drugs may allow higher doses of the two most active agents (carboplatin and etoposide) to be administered.

The TICE regimen was first established in 1990’s at the Memorial Sloan-Kettering Cancer Center. The dosing schedule and safety in 47 patients was first published in 2007r. The TICE regimen consists of 2 cycles of rapidly recycled conventional-dose paclitaxel plus ifosfamide and then G-CSF for stem cell mobilisation followed by 3 cycles of high-dose carboplatin and etoposide, with each high-dose cycle followed by an ASCT. Carboplatin is dosed by AUC. Efficacy and prognostic factor analysis on 107 patients was then published in 2010 by Feldman et alr.This protocol targeted patients predicted to have a poor outcome with salvage CDCT, including patients with extragonadal primary tumour site; progression after a prior salvage CDCT regimen; or an incomplete response or relapse within <6 months after first-line chemotherapy. There were 54 (50%) complete and eight (8%) partial responses with negative markers; 5-year DFS was 47% and OS was 52% (median follow-up, 61 months). No relapses occurred after 2 years. Five (24%) of 21 primary mediastinal non-seminomatous GCTs are continuously disease free. See Figure 1 below under Efficacy for Disease Free and Overall Kaplan-Meier Survival curves.

Note there is a current actively recruiting randomised phase III study comparing the TICE regimen with conventional dose chemotherapy using paclitaxel, ifosfamide and cisplatin (TIP) as first salvage treatment in relapsed or refractory germ cell tumours. Please see link for more information.

Toxicity

The toxic effects of high-dose chemotherapy were primarily myelosuppression, mucositis, nausea, vomiting, dehydration, peripheral neuropathy, and otologic abnormalities. There were two (2%) treatment-related deaths including one fatal cerebral haemorrhage and one fatal pulmonary haemorrhage. Ototoxicity, an important toxicity connected with high-dose carboplatin treatment that is especially relevant in a patient population previously treated with cisplatin-based therapy, was seen in some patients. Hearing loss was most significant at higher frequency levels, although moderate changes in hearing at the speech-range frequencies were seenr.

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